Introduction: Who Should Undergo Diagnostics

Leber’s congenital amaurosis, often called LCA, is typically present from the moment a baby is born, though parents may not notice anything unusual right away. Many babies with this condition begin showing signs within their first few months of life. If you notice that your infant doesn’t seem to respond to visual cues, doesn’t make eye contact, or doesn’t follow moving objects with their eyes, these could be early warning signs that something is affecting their vision.^[1]

One of the most characteristic behaviors parents often notice is their baby frequently rubbing or poking at their eyes with their fists or fingers, even when they aren’t tired. While all babies rub their eyes sometimes, children with LCA do this much more often because the pressure creates flashes of light that their damaged retinas can produce. This behavior is so common in LCA that doctors have a special name for it: Franceschetti’s oculo-digital sign.^[2]

You might also observe other concerning signs in your baby’s eyes. Their eyes may shake or move rapidly in an involuntary way, which doctors call nystagmus. The eyes might not be properly aligned, pointing in different directions, a condition known as strabismus. Your baby may also seem unusually bothered by bright light, squinting or turning away from it more than other babies do. This sensitivity to light is called photophobia.^[2]

Another important clue is how your baby’s pupils react to changes in light. Normally, pupils get smaller in bright light and larger in dim light, adjusting quickly as lighting conditions change. In babies with LCA, this pupil response is either very slow or doesn’t happen at all. An eye doctor can check this during an examination.^[1]

Some forms of LCA affect vision from the very beginning, with babies showing profound visual impairment or even complete blindness at birth. About one in three babies born with LCA has blindness from birth. Other forms may not affect vision until the baby is around six months old, giving parents a few months before they notice problems. In rarer cases, some types of LCA caused by specific gene changes, such as those involving the RPE65 gene, may affect night vision first before progressing to impact vision under all lighting conditions.^[4][5]

It’s worth knowing that LCA occurs in approximately 2 to 3 out of every 100,000 newborns, making it quite rare. However, among children who are blind or severely visually impaired, LCA is one of the most common causes. It accounts for about 5 percent of all inherited retinal diseases and roughly 20 percent of blindness in school-age children.^[1][4]

Diagnostic Methods

When you bring your baby or child to see an eye care specialist, they will begin with a thorough eye examination. This includes looking at the outside of your child’s eyes as well as examining the inside structures. The doctor will check how the eyes move, how the pupils respond to light, and whether the eyes are properly aligned. They’ll also look at the back of the eye where the retina is located—the light-sensitive tissue that’s affected in LCA.^[2]

Interestingly, when doctors first examine babies with LCA, the retina often looks relatively normal. This can be confusing because even though the retina appears fine, it isn’t working properly. As children with LCA grow older, changes become more visible. The retina may show thinning, unusual pigment patterns that look speckled or show bone-like shapes, and the blood vessels in the retina may become narrower than normal. The optic nerve, which carries signals from the eye to the brain, may also appear pale.^[5][8]

Because the appearance of the retina alone isn’t enough to confirm LCA, especially in very young babies, doctors rely on a special test called an electroretinogram, or ERG. This test is crucial for diagnosing LCA and is often considered essential for confirming the condition. The ERG measures the electrical activity in the retina to see how well it’s working.^[3]

During an ERG test, your child’s eyes will first be dilated with special eye drops to make the pupils larger. Then, a special contact lens is placed on each eye to measure how the retina responds to different types and amounts of light. The test checks the retina’s function under various lighting conditions to determine which parts aren’t working normally. In children with LCA, the ERG typically shows very little or no electrical activity, sometimes described as a “flat” ERG, meaning the retina is barely functioning or not functioning at all.^[4][5]

Your child’s eye doctor may also perform an optical coherence tomography scan, known as an OCT. This is a non-invasive imaging test that uses reflected light to create detailed pictures of the back of your child’s eyes, including the retina’s layers. This helps the doctor see the structure of the retina in great detail and can show changes that aren’t visible during a regular eye examination.^[2]

After the initial eye tests suggest LCA, genetic testing becomes very important. LCA can be caused by changes in almost 30 different genes, and knowing which specific gene is involved can help doctors predict how the disease might progress and whether your child might be eligible for certain treatments. Genetic testing is done through a blood sample, and the results can identify which gene mutation is causing your child’s LCA.^[5][8]

The most common genes associated with LCA are CEP290, CRB1, GUCY2D, and RPE65. However, despite testing for all known LCA genes, about 30 percent of people with LCA still don’t have an identified genetic cause, suggesting there are other genes that researchers haven’t discovered yet.^[1][3]

Because LCA can sometimes be confused with other eye conditions that affect children’s vision, your child’s eye specialist may need to rule out other possibilities. This process is called a differential diagnosis. Conditions they might check for include color blindness, drooping eyelids (ptosis), retinitis pigmentosa (another inherited retinal disease that usually appears later in childhood or adulthood), and several genetic syndromes that affect multiple body systems, such as Joubert syndrome and Zellweger syndrome.^[2]

Genetic counseling is an important part of the diagnostic process. A genetic counselor can help you and your family understand how LCA is inherited and what it means for your child and any future children you might have. Since LCA is almost always inherited in an autosomal recessive pattern, both parents typically carry one copy of a changed gene but don’t have vision problems themselves. Each child of two carrier parents has a 25 percent chance of inheriting both changed genes and developing LCA.^[1][5]

In some rare cases, certain gene mutations that cause LCA can also affect other parts of the body beyond the eyes. Some children may have developmental delays, kidney problems, or other health issues. For this reason, it’s important for children diagnosed with LCA to be evaluated by a pediatrician who has experience with inherited diseases. This ensures that any other health concerns are identified and addressed early.^[5][8]

Diagnostics for Clinical Trial Qualification

When researchers develop new treatments for LCA, including experimental gene therapies, they need to carefully select which patients can participate in clinical trials. The diagnostic tests used to qualify patients for these studies are similar to those used for regular diagnosis but often involve additional detailed evaluations.

First and foremost, clinical trials require genetic testing to confirm not only that a patient has LCA but also to identify the exact gene mutation involved. Many clinical trials are designed to treat specific genetic forms of LCA. For example, trials testing gene therapy for mutations in the RPE65 gene can only accept patients who have confirmed mutations in both copies of that specific gene. Similarly, trials for CEP290, LCA5, GUCY2D, or other gene mutations require genetic confirmation before enrollment.^[5][11]

Clinical trials also require baseline ERG testing to document how much retinal function the patient has before treatment begins. The ERG provides objective measurements of electrical activity in the retina, which helps researchers determine whether the treatment is working by comparing results before and after therapy. Even though many LCA patients have very low or flat ERG readings, these baseline measurements are still recorded.^[5]

Vision function testing is another key component of clinical trial qualification. Researchers need to measure how much vision a patient has at the start of the study. For patients with some remaining vision, standard vision tests might include reading eye charts or using special equipment to measure visual acuity (how clearly they can see). However, many children with LCA cannot perform standard vision tests because their vision is too severely impaired.^[5]

For clinical trials of gene therapy, researchers have developed special vision tests designed for people with very limited sight. One important test is called multi-luminance mobility testing, or MLMT. In this test, patients navigate through an obstacle course under different lighting conditions—from bright light to very dim light. Researchers measure how well patients can move through the course without bumping into obstacles, which gives a practical measure of their functional vision. This test has been used in clinical trials for RPE65 gene therapy to show whether patients’ vision improved after treatment.^[5][8]

Imaging tests like OCT scans may also be required for clinical trial enrollment. These scans show the structure of the retina in detail, helping researchers understand how much retinal tissue remains. For gene therapy to work, there need to be enough living retinal cells to receive and benefit from the treatment. If the retina has degenerated too much, with too few cells remaining, gene therapy may not be effective.^[2]

Some clinical trials have age requirements, accepting only patients within certain age ranges. For instance, some trials may focus on young children whose retinas still have relatively intact structure, while others might include older children or adults. The exact requirements vary depending on the trial’s goals and what researchers are trying to learn about the treatment.^[10][11]

Documentation of disease progression may also be required. This involves comparing eye examinations and vision tests done at different times to understand how quickly the patient’s vision has been declining. Some trials want to enroll patients whose disease is progressing at a certain rate, while others may have different criteria.

Patients interested in clinical trials should also be prepared for detailed medical history reviews. Researchers need to know about any other health conditions, medications being taken, and past medical treatments. Because some gene mutations that cause LCA can affect other body systems, comprehensive health screening may be necessary to ensure patients meet all trial requirements and that it’s safe for them to participate.